CA2076023A1 - Use of 5-trans prostaglandin f as an ocular hypotensive agent - Google Patents

Abstract

The invention relates to a means of reducing or maintaining intraocular pressure, and, more particularly, to a method and composition for reducing or maintaining intraocular pressure involving the administration of a composition containing 5-trans prostaglandin F2.alpha. in a pharmaceutically acceptable carrier.

Description

WO91/1~28 PCT/VS91/00986 U8~ OF S-~RAN~ pRo8~AaLANDIN F~ 2 0 7 6 0 2 3 A~ AN OC~AR ~YPOT~N8IV~ AG~NT
Field o the Invention The present invention relates to a means of reducing or maintaining intraocular pressure, and, more particularly, to a method and composition for reducing or maintaining intraocular pressure involving the administration of a composition containing 5-trans prostaglandin F2~ in a pharmaceutically acceptable carrier.
Bac~qround of the Invention The compositions and method of the present invention are particularly useful for the management of glaucoma, a disease 15 of the eye characterized ~y increased intraocular pressure.
On the basis of its etiology, glaucoma has been classified as primary or secon~ary. For example, primary glaucoma in adul~s (congenital gl~ucoma) may ~ ~ith~r open-angl~ or acut~
or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor oran enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chambQr and its anatomic structures appear normal, but drainage of thæ aqueous humor is impeded.
In acute or chronic anglQ-closurs glaucoma, the anterior chamber is shallow, the filtration a~gle is narrowed, and the iri8 may obstruct the trabecular meshwork at the entrance of th~ c~n~l o~ Schlemm. Dilation o~ the pupil may push the root of iri~ forward again~t the angle, and may produce pupillary blo~X and thus precipitate ~n acu~e attack. Ey~s w~th narrow anterior chamber angles are pred$spo~ed to acute angle-closure glaucoma attack~ o~ ~arious degree o~ ~everity.
Secondary glaucoma i8 cau~ed by any interfQrence ~ith the - flow of aqueous humor ~ro~ the po~terior chamber into the anterior cha~ber and subsequently, into the canal Or Schlemm.
In~lammatory disease of th~ anterior segment may pr~vent aqueous escape by causing complate posterior ~yn~chia in irls bombe, and may plug the drainage channel with exudates. Other common causes are intraocular ~umors, enlarged cataracts, ..

~ u ~ u ~
WO91/1~28 -2- ~CT/US91/00986 _ central retinal vein occlusion, trauma to the eye, operat~ve procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2%
of all persons over the age of 40 and may be asymptotic for S years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical ~-adrPnoreceptor anta~onists have tradltionally been the drugs of c~oice for treating glaucoma.
Certain eicosanoids and their derivatives have been ~0 reported to possess ocular hypotensive activity, and have ~een recommended for use in glaucoma management. Eicosanoi~s and derivative include numerous biologically important compounds such as Prostaglandins and their derivatives. Prostaglandins can be described as derivatives of prostanoic acid which has the following structural formula:

~8"~`~COO~t Various types of Prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostano~c acid sk~leton. ~urther classificatio~ is bas~d on the nu~ber of unsaturated bond~ in the side chain indicated by numer~c~l subacripts after the generic typQ of Prostaglandin [e.q~Prostaglandin E1 ~PGE1), Pro3taglandin E2 ~PGE2)~, and on th~ con~$guration of th~ substituents on the alicyclic rlng ind~cated ~y ~ or B [e.g. Pro~tagland~n F2~(PGF2~
Prostaglandins were -earlier regarded as potent ocular hypertQn~ive~, however, e~idenco acc~mulated in ths last d~cade show that ~o~e prostaglandins are highly Q~ectivQ ocular hypotensiv~ agents, and ar~ ideally suited for tho long-term ~edical management o~ glauco~a (SQe~ Por ~xample, Bito, L. Z.
B1QLoa~ca~ Protection With Prostaalandins Cohen, M. M., ed., Boca Raton, Fla, CRC Press Inc., 1985, pp. 231-252; and ~ito, L. Z., A~çd Phar~açoloq~ the Med.ical ~reatment of laucomas Drance, S. M. and Neufeld, A. H. eds., New Yor~, .

~v ~v:~
WO9l/1~2X -3- PCT/US91/00986 ,, ' Grune ~ stratton, 1984, pp. 477-s05). such Prostaglandi~
include PGF2~, PGF~l, PGE2, and certain lipid-soluble esters, such as c1 to c2 al~yl esters, e.g. l-isopropyl ester, o~ such compounds.
Although the precise mechanism is not yet known, recent experimental results indicate that the Prostaglandin-induced reduction in intraocular pressure results from increased oveoscleral outflow [Nilsson et al., Invest. o~hthalmol. Vi5.
Sci. 28(suppl), 284 (1987)~.
The isopropyl ester o~ P6F2~ has been shown to have significantly greater hypotensive potency than the parent compound, presumably as a result of its more e~fective transfer through the cornea. In 1987 thi~ compound was described as "the most potent ocular hypotensive agent ever reported" [see, for example, Bito, L. Z., Arch. O~hthal~ol. ~Q~, 1036 (1987), and Siebold et al., ~g~xuq ~, 3 (1989)].
Whereas Prostaglandins app~ar to be devo~d o~ signi~icant intraocular side effects, ocular sur~ace ~con~unctival~
hyperemia and foreign-~ody sensation have been consistently associated with the top$cal ocular use of such compounds, in particular PGF2a and its prodrugs, e.g. its l-isopropyl ester, in humans. The clinical potentials of Prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma are greatly limited by these side effects.
In a series of co-pending Unitet States patent applications assigned to Allergan, Inc. Pro~taglandin esters with increased ocular hypotensive activity accompanied with no or substantially reduced siae-effects are disclosQd. Th~ co-pending USSN 386,835 (filed 27 July 1989), relate~ to c~rtainll-acyl-Prostaglandlns, such a~ ll-pivaloyl, ll-acetyl, 11-isobutyryl, ll-valeryl, and ll-isovalQryl PGF~. Intrao~ular pressure reducing 15-acyl Pro~taglandin~ are disclosed in the co-panding application USSN 357,394 (~ilod 25 May 1989).
Si~ilarly, 11,15- 9,15- and 9,11-diRsters of Prostaglandins, for example 11,15-dipivaloyl PGF2Q ar~ known to have ocular hypotensive activity. Seo the co-panding patent applications USSN No~. 385,645, 386,312 and 386,83~ (all ~iled 27 July 1989). Ths disclosure~ of all of these patent applications are hereby expressly incorporated by refer~nce.

. . .
, WO91~1~28 ~4~ PCTtusgl0o796Q 2 3 -- summarY o~ the InventiQ~
The present invention relates to the use of 5-trans Prostaglandin F2~, ormulated in a pharmaceutically acceptable vehicle, for the treatment of glaucoma and ocular hypertension.
Quite surprisingly,. 5~trans Prostaglandin F2~, where the 5-6 d~uble bond is in the trans rather than the natural cis configuration, has pronounced ocular hypotensive activity with significantly reduced adverse side effects, notably ocular surface hyperemia. 5-trans Prostaglandin F2~ is, therefore, excellent candidate for therapeutic treatment of a variety of ocular hypertensive conditions such as open-angle glaucoma, closed-angle glaucoma, ocular hypertensive episodes, post-surgical and post-laser trabeculectomy, and as a presurgical adjuvant.
In accordance with another aspect of the present invention, there is provided a. topically applicable pharmaceutical composition for treating ocular hypertension which comprises 5-trans Prostaglandin F2~ of the formula (I):
HO ~OOH

HO
or a salt thereo~ prQsent in a pharmaceutically acceptable excipient, in a therapeutlcally eSSective amount. The therapeutically e~fective amount usually i~ within the range of approximately 0.0001% to 5%. Optionally, the composition of the pr~sQnt invention may further comprise co-~olvent~, p~
bu~f-~, v~scosity ~nhancers, antiblotics or other advantageous ad~uY~Dt~.
In accorda~c~ with a further aspQct of the present inv~ntion, th~re i5 provided a method o~ treating ocular hyperten3~0n which comprlses administering to a mammal having ocular hyperten~ion a th~r~p~utlcally e~ectiv~ ~ount o~ 5-trans Pro~taglandtn PGP2~; or a pharmacout~cally acc-ptabl- salt thereo~.
In a rurther aspect, the present invention relat~s to an ophthalmic solution comprising a therapeutically e~fective amount o~ PGF2~, or a pharmaceutically accep~able salt thereof, in admixture with a ~on-toxic, ophthal~cally acceptable llquid W091/1~28 ~5~ PCT/US91/0~ 2 3 vehicle, packagQd in a container suitable for metered application.
In a still further aspect, the present invention relates to a pharmaceutical product, comprising a container adapted to dispens~ its contents in metered form; and an ophthalmic solution therein, as herei~above defined.
Further features and advantages of the present invention will ~ecome apparent from thQ detailed description of preferred embodiments which follows, taken together with the examples and claims appended hereto.
De~ailed DescriDtion of the Inventian The present invention relates to the use of PGF22 and pharmaceutically acceptable salts thereof as ocular hypotensives. P~F2~ has the following structural formula (I) HO~ ~ COOH

~ ~0 In the foregoing formula thickened solid line attachment indlcates tA~ beta conflguration. ~he broken llne attachments o~ tho hydroxyl group lndicatQ that the3~ substltuents are in alpha con~iguration.
As hereinabove mentioned, it has been established that PGF2~
lowers intraocular pressure in man and other ma~mals when applled topically to t~e eye. How~ver, topical applica~ion of Prostaglandin F2~ produces ~ide Q~feCts such as con~unctival hyperemia, smarting, and roreign ~ody sensations which range in degree from undesirable to unacceptable, depending upon the particular patient and the do8age necessary to produce a sufficient pressure regulating e~fectO In addi~ion, Prostaglandin ~`2~ may produce tran~ient ocular hypertension.

.
.

~U ~b~
W091/1~28 ~6- PCT/US91/~986 In accorda~ce with the present invention, there has been provid~d an ocular hypotensiye which comprises 5-trans Prostaglandin F21. 5-trans Prostaglandin F2~, where the 5-6 double bond is in the trans configuration, has substantially the same ocular hypotensive activity as natural Prostaglandin F2~ with significantly reduced advers~ side effect-, notably ocular surface hyperemia. Moreover, on a dose-e~fect basis, 5-trans Prostaglandin F~4 is less potent in causing ocular hypertension, an undesirable side-effect in glaucoma therapy.
The PGF2~ compound illustrated in Formula (I) is ,n the free acid form. However, as ~ill be appreciated by one of skill in the art, any of a variety of the corresponding salts may also be utilized in the ophthalmic formulations oS the pr~sent inventinn. Thus, if the carboxylic acid group at C-l of the Formula (I) compound is designated:

~0 ~ COOH
' ~
HO HO

A may be -OH to produce the free acid, or -OR where R may be either the anion component of any of a variety of phar~aceutically acceptable salts. A pharmaceutically acceptable salt is any salt which retain3 the activity o~ the parent compound and does not impart any del~terious or und~rable e~ect on the subject to whiCh it is administered and ~-the context in which it i5 administered.
8uitable pharmaceutically acceptabl~ salt~ may be derived fro~ either an organic or inorganic base. Such a salt may co~prisQ a ~ono- or polyvalent ion. Of particular intQrast are inorganic cations such as sodium, pota~5ium, calcium, magnesium and zinc. Organic salts may b~ mad~ wlth amin~s, particularly ammoniu~ salts such as mono-, di- and trialkyl amin~ or ethanol amines. Salt~ may also be formQd with caffeine, tromathamin~ and similar molecules. Wh~r~ acid addition salts are formed ~rom amine , any inorganic or organic acid may be used. Preferred salts are hydrogsn chlorids ~alts, sulfate salts, phosphatQ ~alts and salts of simpl~ organic acids of 2 .. . . . . . . .
. ; - .

WO9l/1~28 -7- PCT/US91 ~ 8~ 6 ~ 2 3 ! ~ to 6 carbons, either th~ mono- or dlAcids. Qu~ternary ~mmoniu~
compoundq can be prepared ~rom alkylating agent~ such ao methyl iodide and the li~e.
P~armaceutical compositions may be prepared ~y co~bining a S therapeutically efficient amount of 5-trans PGF~ or a pharmaceutically acceptabl~ acid addition salt thereo~, ~g an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipient~, and by pr~paration o~ unit dosage - forms suitable for topical ocular use. The therapeutically efficient a~ount typ~cally is b~tween about 0.0001 and about 5%
(w/v), preferably about 0.001 to about 0.1% (w/v) in liguid formulations.
For ophthalmic application, preferably solutions are prepared using a physiological ~aline ~olutlon as a ma~or vehicle. The pH of such ophthalmic solution~ should pre~erably be maintained between 6.5 and 7.2 with an appropriate bu~fer system. ~he ~ormulation3 ~ay al~o contAin conv~ntional, pharmaceutically acceptable preser~atives and stab~liz~r~.
Preferred préservatives that may be u~ed in thQ
pharmaceutical compositions oZ the presont invention include, but are not limited to, benzalkonium chloridQ, chlorobutanol, thimerosal, phenylmercuric acetatQ and phenylmercuric nitrate.
Likewise, various preferred vehicles may b~ used in the ophthalmic preparat~on~ of the present invQntion. ~hese vehicl~s includ~, but ars not l~mited to, polyvinyl alcohol, povidone, hydroxypropyl mQthyl c~llulo~e, poloxamers, carboxymathyl colluloso, hydroxyothyl c~llulo~Q and purified WZlt~F.
Toniclty ad~ustor~ ~ay b~ add0d a~ n~edad or conv~nient.
Th-y- ~nclud~, but aro not l~tQd to, ~alt-, particularly sodium chloride, pota~sium chlorid~, ~annltol and glycQrln, or any ot~r ~uitablo opt~al~ically acc~pt~bl~ ton~city ad~u~tor.
Variou3 buf~er~ and ~ean~ ~or ad~uffting pFl ~y bo u~ed 50 long as th~ r~ulting pr~paratlon i~ opht~al~cally ~cc-ptabl~.
Accordingly~ bur~er- includ- ac-tat~ buS~-r~, citrat- bu~-r-, pho3phate bu~er~ and borat- buf~or~. Acid~ or b~--s ~ay be used to ad~u~t the pH o~ th~o ~or~ulation- a~ n~ d-d.
In a ~i~ilar v~in, an ophthal~ically acc~pt~bl- antioxidant for use in the pre~ent invention includas, but iB not linited .

W091/1~28 -8- PCT/US91/~986 to, sodium mQtabisul~ite, sodium thio~ulrate, acetylcysteine, butylated hydroxy~ni~ole and butylated hydroxytolue~.
Other excipient component which may be included in the ophthalmic preparation~ are chelating agents. Th~ pr~erred chelating agent is edentate di30dium, although other chQlating agents may also be used in place or in conjunction with it.
The ingredients are usually used in thQ following amounts:
Inaredien~ Amoy ~ % w/v) active ingredient about 0.001-5 praservative 0-0.13 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. p~ 4.5-7.5 antioxidant as needed purified water a~ n~eded to mak~ 100%
The actual dose o~ th~ active compound~ of the prQsent invention d~pend~ on th~ spQci~ic compound, and on thQ
condition to be treatQd: the s~lection o~ thQ appropriatQ do~e is wall within the knowledge o~ the sXillQd artisan.
~ h~ ophth~l~ic ~or3ul~t~on~ of th~ pr~nt invo~tion are conveniently pacXaged in for~s suitable for m~t~red application, ~uch as in containers ~quipped with a dropp~r, to facilitate th~ application to the ey~. Container~ suitabla for dropwi~ application are usually made o~ ~uitablQ inert, non-toxlc plastic material, and gonerally contain betw~en about 0.5 and about 15 ~1 solution.
Tho invention can be ~ore fully appr~ciat~d by the folloNlng ex~pl-.
3C E~a~Eh~:
~xp~r~montal quantltieo o~ 5-trans Prostaglandin F2.
and Pro~tagl~ndin ~ w-r~ pr~par~d by di~olution in 2% ~/v) Na2CC3 wi~h tho p8 ad~u-t~d to 7.0 by O.lN RCl. Exp~rimontal rabbits w~r~ treat~ ~y giving on~ drop to ths ocul~r ~ur~ac~
35 o~ ~ith~r ~ 0.01%, 0.1~ or 1% ~olutlon ~o that thra- treatm-nt group~, each comprlJing 6-8 animal-, w~r- obtalned ~or both 5-; tran~ Prostaglandin F2. and Prostaglandin F~. Intraocular pressur~ was measured by applanation pn~u~latonomatry at th~
time o~ ad~lnistration and at 0.5, 1; 2, ~, 4, and 6 hour~
thereafter. Ocular sur~ac~ hyp~r~a wa~ vi~u~lly ~ao83~d and WO91/1~28 ~9~ PCT/US91/2 ~ 6 ~ ~ 3 f-: described as either ab~ent or present in some degree. The following data were obtained Comparison of the data obtainRd with S-trans Prostaglandin F~ and Prostaglandin F2~ indicates th~t they are S essentially equipotent as an ocular hypotensive agents.
However, Prostaglandin F2~ induced ocular h~potension i3 achieved with a very high incidence of ocular surface hyperemia, whereas for the low (0.01%~ and intermediat~ (0.1%) doses of 5-trans Prostaglandin F28 similar ocular hypotension is ach~eved with mini~al or, in the case oS the 0.1% do8e, no ocular surface hyperamia. Moroover, on a dos--effect basls, 5-tran~ Prostaglandin F2~ is less potent in causing ocular hypertension, an eSfect which i8 considered undesirable in glaucoma therapy.
Although this invention is described herein in terms of certain preferred embodiments, these e~bodiments are intended to illustrate thQ lnvention and not to impose li~its.
Other embodiments that are apparent to tho~e of skill ~n the art are also within the scope oS this ~nvention. Accordingly, the scope oS this invention i~ lntended to b~ defined only by reference to the appended claims.

Claims (6)

WHAT IS CLAIMED IS:

1. Pharmaceutical composition for reducing or maintaining intraocular pressure, comprising a therapeutically effective amount of 5-trans PGF2.alpha. of formula (I) or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable vehicle, in unit dosage form suitable for topical ocular use.

2. The composition of Claim 1 wherein said compound is 5-trans PGF2.alpha..

3. A method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of 5-trans PGF2.alpha. or a pharmaceutically acceptable salt thereof.

4. The method of Claim 3 wherein said compound is 5-trans PGF2.alpha..

5. An ophthalmic solution comprising a-therapeutically effective amount of 5-trans PGF2.alpha. or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle, packaged in a container suitable for metered application.

6. A pharmaceutical product, comprising a container adapted to dispense the contents of said container in metered form; and an ophthalmic solution in said container comprising 5-trans PGF2.alpha., or 2 pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle.